There is considerable evidence indicating that both PI3Kδ enzymes and CD20 contribute individually to tumourigenesis in a wide variety of human cancers and especially in hematological malignancies. The phosphoinositide 3-kinases (PI3Ks) are a family of enzymes that regulate diverse biological functions in every cell type by generating phosphoinositide second-messenger molecules. As the activity of these phosphoinositide second messengers is determined by their phosphorylation state, the kinases and phosphatises that act to modify these lipids are central to the correct execution of intracellular signaling events. PI3Ks phosphorylate lipids at the 3-hydroxyl residue of an inositol ring (Whitman et al., Nature 332:664 (1988)) to generate phosphorylated phospholipids (PIP3s) which act as second messengers recruiting kinases with lipid binding domains (including plekstrin homology (PH) regions), such as Akt and phosphoinositide-dependent kinase-1 (PDK1). Binding of Akt to membrane PIP3s causes the translocation of Akt to the plasma membrane, bringing Akt into contact with PDK1, which is responsible for activating Akt. The tumor-suppressor phosphatase, PTEN (Phosphatase and Tensin homolog deleted on chromosome Ten), dephosphorylates PIP3 and therefore acts as a negative regulator of Akt activation. The PI3-kinases Akt and PDK1 are important in the regulation of many cellular processes including cell cycle regulation, proliferation, survival, apoptosis and motility and are significant components of the molecular mechanisms of diseases such as cancer, diabetes and immune inflammation (Vivanco et al., Nature Rev. Cancer 2:489 (2002); Phillips et al., Cancer 83:41 (1998)).
The PI3Ks family is constituted by four different classes: Classes I, II, III and IV. Classes I-III are lipid kinases and Class IV are serine/threonine protein kinases.
The members of the Class I family of PI3Ks are dimers of a regulatory and a catalytic subunit. The Class I family consists of four isoforms, determined by the 110 kDa catalytic subunits α, β, γ and δ. See Engelman J. A., Nat Rev Genet 7:606-619 (2006); Carnero A., Curr Cancer Drug Targets 8:187-198 (2008); and Vanhaesebroeck B., Trends Biochem Sci 30:194-204 (2005). Class I can be subdivided into two subclasses: Class Ia, formed by the combination of p110 α, β, and δ, and a regulatory subunit (p85, p55 or p50); and Class Ib, formed by p110 γ and p101 regulatory subunits.
Studies regarding PI3K and related protein kinase pathways have been published by various research groups, including, Liu et al., Nature Reviews Drug Discovery 8:627-644 (2009); Nathan et al, Mol. Cancer Ther. 8(1) (2009); and Marone et al., Biochimica et Biophysica Acta 1784:159-185 (2008). Two known PI3K inhibitors, LY294002 and Wortmannin, are non-specific PI3K inhibitors as they do not distinguish the four members of Class I PI3K: α, β, γ, and δ. A number of PI3K inhibitors have entered clinical trials for the treatment of cancers, and various types of cancers, including breast cancer, non-small cell lung cancer (NSCLC), and hematological cancers, are being considered as areas of therapeutic interest.
CD20 is a hydrophobic transmembrane protein with a molecular weight of 35-37 kDa which is present on the surface of mature B lymphocytes. It is expressed during the development of B lymphocyte cells (B cells) as from the early pre-B stage until differentiation into plasmocytes, a stage at which this expression disappears. CD20 is present on both normal B lymphocytes and malignant B cells including most non-Hodgkin's B-cell lymphomas (NHL) and B-type Chronic Lymphocytic Leukemia's (B-CLL). The CD20 antigen is not expressed on haematopoietic stem cells or on plasmocytes.
Anti-CD20 antibodies have been, and continue to be, developed for the treatment of B-cell diseases. Successes have been reported for the anti-CD20 antibody rituximab. However, there are a substantial number of patients who are refractory to treatment with rituximab or who develop resistance in the course of prolonged treatment with rituximab (used as a single agent or even in combination with chemotherapeutic regimens).
Accordingly, there is a need for more effective therapies for the treatment and/or amelioration of diseases or disorders associated with modulation of PI3Kδ enzymes and/or CD20 protein, and in particular for the treatment and or amelioration of B-cell diseases.